Device for measuring eye lens opacity

ABSTRACT

The invention is directed to an apparatus for making in vivo measurements of eye lens cloudiness such as caused by cataracta nuclearis. The lens of the human eye has an inherent fluorescence which corresponds to the cloudiness. The apparatus of the invention includes a projecting device for projecting a slit image onto the eye lens with a monochromatic excitation beam having a wavelength lying in the range of 350 nm-500 nm. The light beam excites the fluorescence in the eye lens to produce a fluorescence light. A measuring device measures the fluorescence light in the wavelength range of 380 nm to 650 nm. A signal processing unit analyzes the fluorescence spectrum to determine the wavelength corresponding to a maximum intensity of the fluorescence spectrum. The signal processing unit includes a memory having a scale of values for eye lens cloudiness and stores an empirically determined table of values of the measured parameters corresponding to the scale values. Actual measured parameters are compared to the table of values to determine the degree of eye lens cloudiness.

FIELD OF THE INVENTION

The invention relates to a process and an apparatus for carrying out theprocess for in vivo measurement of the degree of eye lens opacity orcloudiness, particularly of cataract a nuclearis.

BACKGROUND OF THE INVENTION

Cataracta nuclearis is a frequently occurring eye lens cloudiness inolder persons. In it the density and cloudiness of the central portionof the lens increases as the disease progresses. Parallel therewith adiscoloration of the lenses from light yellow to dark brown occurs.These changes in the lens lead to a partial loss of the capacity to seeor even to blindness. Despite intensive investigations, to date not muchis known about the cause or the molecular mechanism of cataractformation. In Appl. Opt. 10, p.459 ff, it is described that theformation of protein aggregates with high molecular weights areresponsible for lens cloudiness. The discoloration, in contrast, isattributed to the presence of photochemically induced chromophores (S.Lerman in "Altern der Linse" (Aging of the Lens), p.139 ff, Symposiumueber die Augenlinse (Symposium on the Eye Lens), Strassburg (1982)).

The diagnosis of lens cloudiness is usually made by means of aconventional slit lamp investigation. Evaluations about localization ofthe center of mass of the cloudiness as well as the degree of maturityof the cloudiness can hereby be made. Both evaluations are dependent toa substantial extent on subjective estimation of the condition. Up tonow there has been in practice no apparatus available which can be usedin routine operation for an objective determination of lens cloudiness.

Investigations of the fluorescence intensity of individual chromophoreshave been carried out using a modified Scheim plug camera. In thismethod the fluorescence is induced with a relatively wide wavelengthrange in the UV region (300-400 nm) and the fluorescence intensity ismeasured at two discrete wavelengths (440 nm and 520 nm). Unfortunately,detailed evaluations of the degree of cataracta nuclearis also cannot bemade with this method.

To improve the detection sensitivity of methods for detecting minimal,but significant, changes in biological systems, various labels ortracers have been introduced in recent years. Other than radioactivelabels, these are primarily fluorescence labels. All of these labels areforeign to the body and must either be injected or orally administered.Even if they are given only in trace amounts, they still adverselyinfluence the relevant biological system.

For these reasons in recent years fluorophotometry using fluorescein asa label (Firm COHERENT) has been developed for cataract investigations.In addition to the intervention in the biological system, this methodhas the disadvantage that the inducing wavelength depends on thefluorescence wavelength of the fluorescein, and the patient is notpermitted to subject himself to sunlight for an extended period of timeafter the examination since his eyes have become very light sensitivedue to the fluorescein and the possibility of damage cannot be ruledout.

Fluorescein is likewise used for investigation of blood-retina andblood-water barriers or to indicate the microcapillaries of thebackground of the eye. Despite the above-mentioned objections, it is theaccepted method since at present no better processes are available.

Since lens clouding takes place gradually, in most cases the patients inthe beginning do not notice the clouding of the lenses. The physician isfirst sought out in a relatively advanced stage. In no event can theaforementioned methods of examination indicate an exact stage of lensclouding. Usually today four stages are used for its classification, theassignment of which by the treating physician does not always take placeclearly. A substantial reason therefor lies in the fact that noquantitative values can be established for the individual stages andthus the assignment occurs subjectively and arbitrarily. For an exactdetermination of the course of the disease it is therefore absolutelynecessary to be able to make quantitative evaluations, i.e. to establisha direct relation of the diagnostic criteria to the changes in thecataract lens. Special value must thereby be placed on early recognitionin order to prevent further development of the disease or at least todelay it. The conventional slit lamp examination is much too unsensitivefor this.

SUMMARY OF THE INVENTION

The invention is therefore based on the problem of providing a simpleprocess for making a diagnosis with which it is possible to detect evenslight lens changes as early as possible and moreover to be able toexactly determine the degree of cataract formation within a scale whichdescribes the lens changes. The process should be able to be carried outwith an apparatus which is constructed in large measure from knowncomponents which have been proved in eye investigations.

The subject matter of the invention can be brought into context with thefollowing observations made independently of each other, whereby inaddition a conclusion can be made about the causes of cataractformation.

In earlier investigations it was determined that with slight anomaliesin the human tissue system, an additional signal occurs in the electronspin resonance spectrum of the relevant tissue which can be correlatedwith the ascorbyl radical. Since in intact biological systems, ascorbicacid (vitamin C) is present almost exclusively in the reduced state, theanomalies under investigation thus relate to a material exchangedisturbance which affects the vitamin C redox equilibrium and leads tooxidation of the vitamin C from ascorbic acid via the ascorbyl radicalto dehydroascorbic acid. As the illness progresses, the oxidationprocess predominates, as a consequence of which the dehydroascorbic acidis also oxidized. This leads to oxidative decomposition products of thevitamin C, for example, diketogluconic acid up to methyl glyoxal.

In the investigation of the vitamin C oxidation mechanisms, theinteresting observation was made that a vitamin C solution which istransparent when freshly prepared, in the course of time (days to weeks)is discolored from yellow to dark brown and yields a characteristicfluorescence spectrum as the discoloration increases. Cataract lensesundergo a similar discoloration. Since it is known that the lens of theeye contains a high concentration of ascorbic acid, the fluorescencebehavior of the lenses was also investigated based on the similardiscoloration behavior. It was thereby surprisingly determined thatthere is an exact parallelism in the fluorescence behavior of cataractlenses and of vitamin C solutions. With monochromatic excitation between350-500 mn and recording of the fluorescence throughout a specificspectral range up to about 650 nm, freshly produced vitamin C solutionsshow no fluorescence; this also applies to healthy lenses which indeedat 350 nm excitation exhibit a slight natural fluorescence which doesnot occur with longer wave excitation, however, and otherwise exhibitsno characteristic features. The specific fluorescence first developsfurther with increasing discoloration and is characteristic of theexisting degree of discoloration both with regard to intensity as wellas the position (wavelength) of the fluorescence maximum. Sincefluorescence measurement is one of the most sensitive methods ofmeasurement, changes in the lenses upon formation of cataracts can bedetected at a very early stage, and based on the distribution pattern ofthe fluorescence intensities, minute differences between the individualcataract stages can be detected with the process according to theinvention.

The results found in the investigation of vitamin C solutions allow oneto conclude that the increasing development of lens cloudiness anddiscoloration is also due to increasing oxidation of ascorbic acid. Thisrecognition is the basis of the advantages of the process according tothe invention. The patient does not need to be investigated with manyfluorescent substances foreign to the body. The primary fluorescence ofa natural body substance is measured, the degree of oxidation of whichcorresponds to the state of development of the cataract. Theavailability of several fluorescence bands yields further detailedinformation through comparisons of intensities which surely will beuseful in the future for therapeutic purposes, since the fluorescencespectrum likewise indicates the progress and success in treatment. Theprocess is very specific. In the investigated wavelength range (350-500nm for the excitation; 380-650 nm for the recording) interferingfluorescences hardly occur at all. A concentration as small as about 1micromole of oxidized vitamin C can be detected.

BRIEF DESCRIPTION OF THE DRAWINGS

The fluorescence spectra for different excitation wavelengths atvariously advanced cataract stages are illustrated in FIGS. 1 through 3.FIG. 4 shows a schematic representation of a suitable measuring device.

DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The measurement curves illustrated in FIG. 1 were obtained by measuringa yellowish discolored lens. Clearly marked fluorescence spectra occurfor the excitation wavelengths λ_(A) =350 nm, λ_(A) =395 nm and λ_(A)=420 nm. As the excitation wavelength λ_(A) increases, the intensity ofthe fluorescence spectrum decreases. At longer excitation wavelengths nofluorescence spectra can be detected at this stage of cataractformation. On the other hand, a beginning cataract formation can berecognized from the first appearance of a fluorescence spectrum forλ_(A) =350 nm. The wavelength associated with the maximum of thefluorescence spectrum at λ_(A) =350 nm lies at 445 nm in this stage. Fora lesser degree of cataract formation, the maximum is displaced towardlonger wavelengths, as can be determined from the subsequentillustrations.

The measurement illustrated in FIG. 2 is caused by an eye lens which isalready brownish discolored. The total intensity of the fluorescencestrongly increases. For the fluorescence spectrum lying furthest to theleft, which belongs to λ_(A) =350 nm, the recording height was dampenedby a factor of 8 in comparison to FIG. 1. The intensities of the furtherfluorescence spectra were dampened by a factor of 16 in order to obtaina representation comparable to FIG. 1. Noteworthy is the excitation ofthe longer wavelength fluorescence spectra at λ_(A) =470 nm and λ_(A)=500 nm, the intensities of which far exceed those of the fluorescencespectra excited by shorter wavelengths. The maximum of the fluorescencespectrum for λ_(A) =350 nm now lies at about 460 nm.

The tendency which already could be seen in FIG. 2 continues in FIG. 3.The measurement illustrated in this figure is caused by an eye lenswhich is already discolored dark brown. In comparing the illustratedfluorescence spectra it must be kept in mind that the intensity of thefluorescence spectrum excited at λ_(A) =350 nm was reduced by a factorof 16 in comparison to the illustration in FIG. 1, while the twofollowing fluorescence spectra at λ_(A) =395 nm and λ_(A) =420 nm werereduced by a factor of 32 and the two fluorescence spectra at λ_(A) =470nm and λ_(A) =500 nm appearing at the right were reduced by a factor of64 in order to produce a comparable representation within the samefigure. The maximum of the fluorescence spectrum at λ_(A) =350 nm hasbeen displaced further in the longer wave region to λ=470 nm.

The measurements illustrated in FIGS. 1 through 3 make the followingclear. A beginning cataract formation can be recognized from thefluorescence at λ_(A) =350 nm. Through a series of measurements atdifferent degrees of discoloration of cataracta nuclearis a wavelengthscale can be established which is correlated with the visually discernedcolor determinations.

With progressive formation of cataracts, i.e. increasing discoloration,the fluorescence with longer wave excitation sets in gradually and thenincreases more strongly than that with short wave excitation. Besidesthe displacement of the fluorescence maximum, each stage of cataractformation is therefore also characterized by the intensity ratios of thefluorescence maxima at different excitation wavelengths. The wavelengthscale can therefore be supplemented in an advantageous manner,particularly in the range of already visually discernable cataractformation, by one or more typical intensity ratios. Since the intensitychanges corresponding to the illustrations in FIG. 1-3 are substantiallyclearer than the wavelength displacements of the maxima of thefluorescence spectra, a scale set up following these criteria permits astill finer subdivision for quantitative indication of the degree ofcataract formation.

The analog depiction of fluorescence spectra illustrated in FIGS. 1 to 3can be digitalized with the aid of known electronic circuits and canthen be conducted to the memory of a computer for evaluation.

In FIG. 4 an apparatus is schematically illustrated which is puttogether from known components but, however, makes it possible to carryout the process of the invention in a particularly advantageous manner.The optical portion of the measurement device is housed in a housing 10.This is provided with adjustable contact and support surfaces 11,12 onwhich the head of the patient can be supported so that the eye lens 13to be examined is located at the intended measurement location.

The housing advantageously has two openings 14,15 through which, on theone hand, a slit image is projected onto the eye lens 13, and, on theother hand, the stimulated fluorescence light is captured. Through afurther opening, not shown, or with the aid of suitable beam divider inthe illuminating beam path, the position of the slit image on the eyelens can be observed supplementally.

The illuminating beam path contains a light source 16, the emissionspectrum of which contains the required excitation wavelengths insufficient intensity, such as, for example, a xenon high pressure lamp.With the help of a subsequently included monochromizing device (notshown) or a series of interference filters arranged on a slide 17,monochromatic illumination of the slit 18 is produced. The slit isprojected via the optics 19 through the opening 14 onto the lens 13 tobe examined. The optical axis 20 of the excitation beam path isadvantageously at an angle of somewhat under 60 with respect to the axis21 of the eye lens in order to suppress as much as possible interferingfluorescence from tissues which are not of interest.

The fluorescence light stimulated on the eye lens is captured throughthe opening 15 via optics 22 and conducted to a recordingspectrophotometer. This comprises, for example, an inlet slit 23 and acontrollably adjustable bending grate 24 which focuses an image of theinlet slit 23 onto an outlet slit 25. A photoelectric detector 26 isarranged behind the outlet slit 25. The optical axis 27 of the detectorbeam path is advantageously at an angle of less than 90° with respect tothe optical axis 20 of the excitation beam path. The plane extendingbetween the excitation beam path and the detector beam path can bearranged at a desired angle with respect to the eye lens.

The adjustment of the filter slide 17 is advantageously effected througha motor (not shown) with the help of a program control unit 28. It canalso take place manually, however. The bending grate 24 for receivingthe fluorescence spectrum is also advantageously adjusted by a motor,whereby the spectral region to be captured is likewise prescribedthrough the program control unit 28.

The signal given off by the photoelectric detector 26 is conducted to asignal processing circuit 29 with a computer for evaluation. For bettersuppression of the excitation light in the detector beam path and toimprove the signal/noise ratio in the measurement signal, a chopper 30is inserted in the excitation beam path. The evaluation of the signal iscontrolled with the interrupter frequency of the chopper 30 so that thefluorescence signal is received only during the time in which theexcitation beam path is interrupted.

Through the supplemental input of the program control signals for theexcitation filter position and the recording of the fluorescencespectrum in the signal processing circuit 29, an automatic measurementoperation is possible for objective determination of the degree ofcataract formation in the eye lens. The computer associated with thecircuit 29 determines the position and intensity of the maxima of therecorded fluorescence spectra, derives the intensity ratios of thewavelengths λ_(Max), compares them with the scale defining the degree ofcataract formation, and depicts the resulting value on an indicatordevice 31.

I claim:
 1. An apparatus for making an in vivo measurement of eye lenscloudiness such as caused by cataracta nuclearis, the eye lens having aninherent natural fluorescence corresponding to the cloudiness, theapparatus comprising:a device for positioning the head of the patient soas to place the eye in a predetermined fixed position desirable formaking the in vivo measurement; a projecting device for projecting aslit image onto the eye lens, the projecting device including:a lightsource for generating a monochromatic excitation beam of light definingan excitation beam axis and having a wavelength λ_(A) lying in the rangeof 350 nm to 500 nm; imaging means arranged in said beam for forming theslit image; sand optic means for focusing the slit image on the eye soas to excite the natural fluorescence in the eye lens to produce afluorescence light defining a fluorescence light axis; a measuringdevice for measuring said fluorescence light, the measuring deviceincluding:a recording spectrophotometer for recording a fluorescencespectrum in the wavelength range of 380 nm to 650 nm which is longerthan said excitation wavelength λ_(A) ; optic directing means forreceiving said fluorescence light from the eye lens and directing thesame to said recording spectrophotometer; and, signal processing meansfor analyzing the fluorescence spectrum recorded by said recordingspectrophotometer to determine the wavelength λ_(max) corresponding tothe maximum intensity I of said recorded fluorescence spectrum; saidsignal processing means including:a memory having a scale of values foreye lens cloudiness and storing an empirically determined table ofvalues of the measured parameters (λ_(A) and λ_(max)) corresponding tosaid scale of values; and, comparator means for comparing the actualmeasured parameters λ_(A), λ_(max) to said table of values therebydetermining the degree of the eye lens cloudiness.
 2. The apparatus ofclaim 1, comprising: program control means for successively setting twodifferent excitation wavelengths (λ_(A1) and λ_(A2)) and initiating theanalysis of the spectra corresponding to said excitation wavelengths bysaid signal processing means which determines the wavelengths (λ_(max1)and λ_(max2)) corresponding to the maximum intensities (I₁ and I₂) andforms an intensity ratio (I₁ /I₂) from said maximum intensities (I₁ andI₂); and, said table of values stored in said memory also includingempirically determined intensity ratios for corresponding excitationwavelengths.
 3. The apparatus of claim 2, wherein: a third excitationwavelength λ_(A3) is provided having a fluorescence spectrum with amaximum intensity I₃ ; said program control means successively sets thethree excitation wavelengths (λ_(A1), λ_(A2), λ_(A3)) and said signalprocessing means forms intensity ratios I₁ /I₂ and I₂ /I₃ from saidmaximum intensities (I₁, I₂, I₃) corresponding thereto; and, said tableof values is supplemented with said intensity ratios.
 4. The apparatusof claim 3, wherein: at least one of the wavelengths 350 nm, 395 nm, 420nm, 420 nm or 500 nm acts as the excitation wavelength λ_(A) ; and, thefluorescence spectra corresponding to said wavelengths λ_(A) lie in thewavelength regions 380-650 nm, 430-650 nm, 460-650 nm, 490-650 nm and520-650 nm, respectively.
 5. The apparatus of claim 4, said measuringdevice including a circuit arrangement for digitalizing the fluorescencespectra measured by the spectrophotometer.
 6. The apparatus of claim 1,comprising: control circuit means for adjusting the intensity of theexcitation beam of light in dependence on the intensity of thefluorescence light.
 7. The apparatus of claim 1, wherein the eye lensdefines an eye lens axis; and, said excitation beam axis being inclinedwith respect to said eye lens axis and said fluorescence light axis soas to cause interfering fluorescence excited in tissue layers lying infront of and in back of the eye lens to be reduced as far as possible.8. The apparatus of claim 1, said light source including a plurality ofnarrow band interference filters individually placeable into the path ofsaid excitation beam for producing the monochromatic illumination. 9.The apparatus of claim 1, said projecting device including: a chopperfor periodically interrupting said excitation beam and wherein thesignal evaluation is controlled with the interrupter frequency of thechopper so that he fluorescence spectrum is recorded only during thetime in which the excitation beam of light is interrupted.